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#37 Background: Neratinib (HKI-272) irreversibly inhibits the tyrosine kinase receptors, erbB1 (EGFR) and erbB2 (HER2). In a phase 1 study, neratinib was tolerable and demonstrated antitumor activity in patients (pts) with solid tumors, including 8 of 25 evaluable pts with erbB2-positive advanced breast cancer. In this open-label, 2-arm phase 2 study, pts with stage IIIB, IIIC or IV erbB2-positive advanced breast cancer were evaluated to further characterize the safety and efficacy of neratinib.
 Methods: ErbB2 gene amplification in tumor tissue, by FISH was a requirement for study entry. Pts were assigned to arm A if they had prior treatment with trastuzumab and to arm B if they had no prior treatment with trastuzumab or other erbB2-targeted drug. All pts received oral doses of 240 mg of neratinib daily. The primary endpoint was progression-free (PFS) survival rate at 16 weeks (wks).
 Results: Enrollment of 136 pts (arm A: 66 pts; arm B: 70 pts; median age 50 years [range 31-83 years]) was completed in November 2007. Common neratinib-related adverse events (AEs), any grade, were diarrhea (89%), nausea (29%), vomiting (23%), fatigue (16%), and anorexia (15%). Diarrhea was the only ≥grade 3 AE that occurred in ≥5% of pts, 26/136 (19%) total pts, 27% in arm A and 11% in arm B. Dose reductions occurred in 27% total pts, 36% in arm A and 19% in arm B, most commonly because of diarrhea. The main reasons for discontinuation of the study were disease progression (arm A: 74%, arm B: 43%), and AEs (arm A: 8%, arm B: 4%).
 124 pts (arm A: 61 pts, arm B: 63 pts) were evaluable for efficacy based on independent assessment and 131 pts (arm A: 65 pts, arm B: 66 pts) were evaluable based on investigator assessment. The objective response rates (complete or partial response) were 26% (95% CI 16%, 39%) in arm A, 51% (95% CI: 38%, 64%) in arm B for independent assessment and 34% (95% CI: 23%, 47%) in arm A, 62% (95% CI: 49%, 74%) in arm B for investigator assessment. The 16-wk PFS rates were 61% in arm A, 75% in arm B (independent); 57% in arm A, and 78% in arm B (investigator). The median PFS for independent [and investigator assessment] was 23 [22] wks in arm A and 40 [35] wks in arm B.
 Discussion: Neratinib demonstrates robust antitumor activity in pts with erbB2-positive advanced breast cancer, with objective response rates of 26% in pts who had prior treatment with trastuzumab and 51% in pts who had no prior treatment with trastuzumab. Additional updated efficacy and safety data will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 37.

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Background: Four large randomized phase III trials have reported significant improvements in disease-free (DFS) and overall survival for H administered with adjuvant polychemotherapy for HER2-positive high-risk BC. With the success of HER2-targeting, limiting chemotherapy is both reasonable and feasible, particularly for smaller, node-negative tumors. However data are limited. Methods: APT is a single arm three-stage, multicenter, phase II study of TH. Patients (pts) with HER2-positive BC (IHC 3 + and/or FISH amplified at > 2.0) with negative nodes (a single axillary lymph node micrometastasis was allowed) and tumor size < 3 cm were eligible. Pts received T (80 mg/m2) with H (4 mg/kg load ®2 mg/kg) x 12 weekly (w), followed by H x 39 w (2 mg/kg weekly or 6 mg/kg q 3 w). The primary endpoint was DFS. DFS events included invasive local, regional or distant recurrence, contralateral invasive breast cancer and death from any cause. The study had 95% power to distinguish between 3-year failure rates of 9.2% vs. 5% using a Poisson model based on the total patient-years of follow-up (PYFU). Planned interim analyses were designed to stop early for futility at 225 and 800 PYFU, and the regimen would be deemed worthy of further study with <40 failures after 1600 PYFU. All pts who began protocol therapy were included in the analyses. Results: 410 pts were enrolled from September 2007 to September 2010 and 406 began protocol therapy. The median age was 55 (range 24-85 years). Sixty-three percent had ER+ tumors. Three percent of tumors were T1mi; T1a; 20% T1b; 41% T1c, and 9% T2 ≤ 3cm. Six pts had a nodal micrometastasis. 356 pts (88%) completed all 52 wks of therapy, with 24 and 6 pts discontinuing due to protocol-specified or other toxicities, respectively. 358 (89%) completed all 12 weeks of combined TH therapy. The most common grade 3/4 toxicities included: neuropathy (4%), neutropenia (4%), transaminitis (3%), leukopenia (2%), fatigue (2%), and hypersensitivity reactions (2%). Reversible symptomatic CHF (grade 3 left ventricular systolic dysfunction) occurred in 2 patients (0.5%). Because of the limited number of events, the Data Safety Monitoring Board approved release of study results with 1316 PYFU and a median follow-up of 3.2 years. A total of 8 DFS events have been observed: 2 pts with metastatic disease, 2 with ipsilateral axillary recurrences, 3 with new contralateral BC (all HER2-), and 1 patient who died after diagnosis of primary ovarian cancer. Conclusion: This represents the first report of TH as adjuvant therapy for node-negative HER2-positive BC. The regimen appears well tolerated and few recurrences have been observed in the study population to date. An updated analysis of efficacy, including estimates of 3-year DFS, will be presented in December when a total of 1520 PYFU in this cohort is anticipated. Based on these early data, the TH regimen may be an acceptable treatment approach for low risk HER2-positive breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-04.